Cyclosporin A activates human hepatocellular carcinoma (HepG2 cells) proliferation: implication of EGFR-mediated ERK1/2 signaling pathway

Fetoh, Mohammed E Abo-El; Helal, Gouda K.; Saleh, Ibrahim G.; Ewees, Mohamed G; El-Shafey, Mohamed; Elnagar, Mohamed R.; Akool, El-Sayed

doi:10.1007/s00210-019-01798-w

Cited by 9 publications

(10 citation statements)

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“…Alteration of the ERK signaling pathway via knockout of ERK2 can reduce hepatic fibrosis and inflammatory response [50]. Moreover, in patients with liver cirrhosis and HCC, the overexpression of Raf, MEK, and ERK has also been detected [51], suggesting the overactivation of ERK in hepatic fibrosis, liver cirrhosis, and HCC. It has also been found that simultaneous activation of the ERK and AKT(Serine/threonine kinase) pathways enhances the cell cycle progression of HBV replicating hepatocytes [50] and that the ERK pathway participates in HBX(Hepatitis B virus X protein)-mediated HCC cell proliferation and migration [52].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Based Exploration on the Intervention of Qinghao Biejia Decoction on the Inflammation-Carcinoma Transformation Process of Chronic Liver Disease via MAPK and PI3k/AKT Pathway

Cheng

Han

et al. 2022

BioMed Research International

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Chronic liver disease(CLD) is a slow-developing and long-term disease that can cause serious damage to the liver. Thus far, it has been associated with viral hepatitis, non-alcoholic fatty liver disease(NAFLD), alcoholic liver disease(ALD), hepatic fibrosis(HF), liver cirrhosis (LC), and liver cancer. Qinghao Biejia Decoction (QBD) is a classic ancient Chinese herbal prescription with strong immune-enhancing, anti-inflammatory, and anti-tumor effects. In this study, we used a network pharmacology approach to investigate the molecular mechanisms of QBD in the inflammation-carcinoma transformation process of chronic liver disease. Two key drug targets, MAPK1 and PIK3CA, were screened using network pharmacology and molecular docking techniques, revealing dihydroartemisinin, artesunate, 12-O-Nicotinoylisolineolone, caffeic acid, and diincarvilone A as active ingredients involved in QBD mechanisms. The main signaling pathways involved were the PI3K-AKT signaling pathway and MAPK signaling pathway. In summary, our results indicated that QBD affects the inflammatory transformation of chronic liver disease through MAPK1 and PIK3CA and signaling pathways MAPK and PI3K/AKT. These data provide research direction for investigating the mechanisms underlying the inflammation-carcinoma transformation process in QBD for chronic liver disease.

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Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Based Exploration on the Intervention of Qinghao Biejia Decoction on the Inflammation-Carcinoma Transformation Process of Chronic Liver Disease via MAPK and PI3k/AKT Pathway

Cheng

Han

et al. 2022

BioMed Research International

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“…Based on the findings of Abo-El Fetoh et al . , phosphorylated ERK (p-ERK1/2) trans-locates from the cytosol to the nucleus (Abo-El Fetoh et al 2020 ). p-ERK1/2 induces the expression of cell proliferation genes (i.e., cyclin D1 and anti-apoptotic Bcl-2) and abrogates the expression of pro-apoptotic Bax.…”

Section: Discussionmentioning

confidence: 99%

“…The protein levels of p-ERK1/2, T-ERK1/2, p-EGFR, and T-EGFR were assessed using western blotting. First, SDS lysis buffer was freshly prepared by adding the following components; 10 mM Tris, 100 mM NaCl, 25 mM ethylene-diamine tetra-acetic acid (EDTA), 25 mM ethylene glycol bis(2-aminoethyl) tetra-acetic acid (EGTA), 0.1% sodium dodecyl sulfate (SDS), 2% (v/v) Triton X-100 (pH 7.4), with 1:1000 protease inhibitor cocktail and phosphatase inhibitors (Elnagar et al 2018 ; Abo-El Fetoh et al 2020 ). Prostatic homogenates were then prepared in SDS buffer and subjected to SDS–polyacrylamide gel electrophoresis and western blotting analysis as described previously (Burnette 1981 ).…”

Section: Methodsmentioning

confidence: 99%

“…Enhanced chemiluminescence (ECL) solution (Perkin Elmer, Waltham ® , Massachusetts, USA) was used to detect the signals with ChemiDoc imager (Bio-Rad ® , California, USA) and the band intensity was measured using ImageLab ® analysis software (Version 6.1.0 build 7, California, USA). T-ERK1/2 and T-EGFR were considered as loading control proteins, as discussed previously (Taylor et al 2013 ; Abo-El Fetoh et al 2020 ).…”

Section: Methodsmentioning

confidence: 99%

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Cyclooxygenase-2 activates EGFR–ERK1/2 pathway via PGE2-mediated ADAM-17 signaling in testosterone-induced benign prostatic hyperplasia

et al. 2022

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Objective and design Prostatic inflammation is the driving force in benign prostatic hyperplasia (BPH). This work investigated the potential modulatory effect of COX-2 inhibition on ADAM-17/EGFR/ERK1/2 axis. Materials or subjects Adult male Wistar rats were used. Treatment Celecoxib (10 and 20 mg/kg; i.p.) was injected i.p. daily for three weeks. Testosterone (TST) (3 mg/kg; s.c.) was used to induce BPH. Methods Prostatic inflammation and hyperplasia were assessed by organ weight and histopathology. Inflammatory mediators were measured using ELISA technique. Protein analysis was performed using western blotting and immunohistochemistry. Gene expression analysis was performed using qRT-PCR. Statistical analyses included one-way ANOVA and Tukey’s multiple comparison test. Results Testosterone-treated rats had a marked increase in COX-2, prostate weight, and index. Moreover, TST-induced COX-2 was inferred from cytoskeletal changes and was attributable to the overexpression of PGE2, NF-κB (p65), and IL-6. COX-2-derived PGE2 increased the activity of ADAM-17, TGF-α, and TNF-α. Consequently, EGFR–ERK1/2 pathway was over-activated, disrupting anti-apoptotic Bcl-2, cyclin D1, and pro-apoptotic Bax. Celecoxib reversed these effects. Conclusion COX-2 stimulates the ERK1/2 pathway via PGE2–ADAM-17-catalyzed shedding of TGF-α in testosterone-induced BPH. The results indicate a functional correlation between inflammation and hyperplasia in BPH.

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“…Phosphorylated ERK1/2 (p‐ERK1/2) is eventually translocated into the nucleus, where it promotes cell proliferation and inflammation. [ 24–29 ]…”

Section: Introductionmentioning

confidence: 99%

Probenecid ameliorates testosterone‐induced benign prostatic hyperplasia: Implications of PGE‐2 on ADAM‐17/EGFR/ERK1/2 signaling cascade

Abdel-Fattah

Fetoh

Afify

et al. 2023

J Biochem & Molecular Tox

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Benign prostatic hyperplasia (BPH) is one of the most prevalent clinical disorders in the elderly. Probenecid (Prob) is a well‐known FDA‐approved therapy for gout owing to its uricosuric effect. The present study evaluated the use of Prob for BPH as a COX‐2 inhibitor. Prob (100 and 200 mg/kg) was intraperitoneally injected into male Wistar rats daily for 3 weeks. In the second week, testosterone (3 mg/kg) was subcutaneously injected to induce BPH. Compared with BPH‐induced rats, Prob treatment reduced prostate weight and index and improved histopathological architecture. The protease activity of ADAM‐17/TACE and its ligands (TGF‐α and TNF‐α) were regulated by prob, which in turn abolished EGFR phosphorylation, and several inflammatory mediators (COX‐2, PGE2, NF‐κB (p65), and IL‐6) were suppressed. By reducing the nuclear import of extracellular regulated kinase protein 1/2 (ERK1/2), Prob helped re‐establish the usual equilibrium between antiapoptotic proteins like Bcl‐2 and cyclin D1 and proapoptotic proteins like Bax. All of these data point to Prob as a promising treatment for BPH because of its ability to inhibit COX‐2‐syntheiszed PGE2 and control the ADAM‐17/TGF‐α‐induced EGFR/ERK1/2 signaling cascade. These findings might help to repurpose Prob for the treatment of BPH.

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Cyclosporin A activates human hepatocellular carcinoma (HepG2 cells) proliferation: implication of EGFR-mediated ERK1/2 signaling pathway

Cited by 9 publications

References 43 publications

Network Pharmacology-Based Exploration on the Intervention of Qinghao Biejia Decoction on the Inflammation-Carcinoma Transformation Process of Chronic Liver Disease via MAPK and PI3k/AKT Pathway

Network Pharmacology-Based Exploration on the Intervention of Qinghao Biejia Decoction on the Inflammation-Carcinoma Transformation Process of Chronic Liver Disease via MAPK and PI3k/AKT Pathway

Cyclooxygenase-2 activates EGFR–ERK1/2 pathway via PGE2-mediated ADAM-17 signaling in testosterone-induced benign prostatic hyperplasia

Probenecid ameliorates testosterone‐induced benign prostatic hyperplasia: Implications of PGE‐2 on ADAM‐17/EGFR/ERK1/2 signaling cascade

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